Pharmacodynamics

“What the drug does to the body”

Introduction:

Pharmacodynamics is the study of the intrinsic sensitivity or responsiveness of receptors

(usually) to a drug and the mechanisms by which these effects occur.

Drug interactions with targets:

In very broad terms, drugs may exert their effect(s) via:

 Physico-chemical interactions (eg antacids, possibly volatile general anaesthetics)

 Interaction with proteins:
- Receptors (lots)
- Enzymes (eg neostigmine)
- Ion channels (eg Calcium channel blockers)
- Carrier molecules (eg Tricyclic antidepressants)

We will mainly look at drug-receptor interaction this lecture, but briefly a note on:

 Physico-chemical interaction:

 Due to Chemical properties: eg Antacids and chelating agents (desferrioxamine,

dicobalt edetate, tetracyclines, Sugammadex etc)
 Due to Physicochemical properties: Both LA’s and volatile agents may act by
producing non-specific changes in the lipid or protein components, which affect
the diameter of ion channels in the neuronal membrane. However, evidence exist
that for LA, interaction with a receptor occurs at the internal aspect of voltage-
gated sodium ch’s  decrease in diameter   Na conductance.
Volatiles may affect neuronal proteins in the brain in a relatively selective way.

 Enzyme inhibition: eg neostigmine vs AchE, aminophyline, milrinone inhib

phosphodiesterase ( c-AMP) NSAID’s inhib cyclo-oxygenase, captopril, enalapril inhib ACE etc
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Terminology: ( with regard to drug responses)

- hyperactive: unusually low dose produces expected pharmacologic effect

- hypersensitivity: allergy to a drug
- hyporeactivity: unusually large dose required to give expected effect
- tolerance: hyporeactivity due to chronic exposure to drug. Cross-tolerance is
common b/w drugs that produce similar effects (eg alcohol + volatiles).
- Tachyphylaxis: tolerance that develops acutely; reflects cellular tolerance.
Note that tolerance/tachyphylaxis may be due to pharmacokinetic as well as
pharmacodynamic causes.
- Additive: two drugs interact to produce an effect equal to the algebraic
summation (eg LA’s, volatiles) eg 1+1 = 2
- Synergistic: 2 drugs interact to produce an effect greater than algebraic
summation. Eg 1+1 = 4
- Agonist (full): a drug that activates a receptor by binding to it (can achieve
max effect)
- Partial agonist (PA): drug that binds to a receptor and produces sub maximal
effect (lower intrinsic activity).
- Antagonist: drug that binds to receptor without activating it and, at the same
time, prevents an agonist from stimulating it.
- Reversible Competitive antagonism: when increasing [ ]’s of an agonist can
overcome the effects of an antagonist
- Irreversible Competitive and Noncompetitive antagonism: when increasing
[ ]’s of an agonist cannot overcome the effects of an antagonist.
- Potency: ability of a drug to produce a certain effect. Influenced by
pharmacokinetics (A,D,M,E) as well as affinity for receptor. Very potent
drugs are effective in very small dose ( see dose-response curves later).
- Efficacy: relates to the intrinsic activity of a drug and determines the maximal
effect attainable by a drug ( = NB not to confuse potency with efficacy and
affinity with intrinsic activity. Dose response curves are an easy way to
explain the difference to yourself and someone else, eg examiners )
- Receptor: Is a component of a cell (usually a protein) that interacts selectively
with an extracellular compound to initiate a cascade of biochemical events that
result in the observed effects of the compound.
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Drug interaction with Receptors:

Receptor: Is a component of a cell (usually a protein) that interacts selectively with an

extracellular compound to initiate a cascade of biochemical events that result in the
observed effects of the compound (Miller’s Anesthesia).

Refer to “Cellular physiology” for classification + detail of families, but briefly:

Types of receptor families:

Type 1 Type2 Type3 Type4

Ligand-gated ion ch’s G-prot coupled Kinase-linked Nuclear

(ionotropic) (metabotropic)

Location membrane membrane membrane intracellular

Effector ion channel Ch or enzyme enzyme gene transcription

2nd msgr -- c-AMP/c-GMP -- --

IP3 / DAG

Coupling direct G-prot direct via DNA

E.g.’s n-AchR m-AchR Insulin steroid , thyroid H

GABAA adrenoceptors growth factor receptors
NMDA Cytokine r’s

Time millisec’s seconds hrs hrs

(fast synaptic)

Structure oligomeric assembly Monomeric with Single trans- Monomeric str with
of subunits around 7 transmembrane membr helix separate R and DNA
central pore helices linking EC R binding domains.
domain to IC
kinase domain
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Drug-receptor interaction

Classical theory:

 Note that binding and activation = two distinct steps in the generation of a receptor-
mediated response by an agonist (A).
 A drug that binds, without causing activation = antagonist (prevents agonist from
binding).
 Tendency of drug to bind to the R = determined by its affinity. Drugs with high potency,
will generally have high affinity for R (see below other factors).
 Tendency for it, once bound, to activate the R = determined by its efficacy. A true
antagonist will have zero efficacy, whereas a full agonist will yield a maximal response
with full receptor occupancy. Drugs with intermediate levels of efficacy, ie response is
submaximal even at 100% R occupancy, are termed partial agonists (see later “two-state
model” for an alternative explanation of above, as well as for inverse agonists).
 Don’t confuse affinity with efficacy: ie two drugs may have same affinity for receptor,
but may produce different levels of activation of the Receptor. Both are agonists, but the
one that can produce maximal activation is a full agonist (ie high intrinsic activity) and
the one that produce less than maximal activation = partial agonist (see also “two-state”
receptor hypothesis).
Note: A partial agonist might even have higher affinity for R than the full agonist (ie =
more potent), but can never reach maximum effect ( eg Buprenorphine vs morphine).
 Thus, the simplest formulation (as opposed to the two-state theory) envisages that the
occupied R can switch from its “resting” state ( R ) to an activated state ( R* ). R* being
favoured by binding of an agonist but not an antagonist.
 The tendency for the occupied receptor, AR, to convert to the activated form, AR*, will
depend on the equilibrium constant for this reaction, / (= measure of intrinsic activity
and thus efficacy).
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 For a pure antagonist, / = 0, whereas for an agonist it has a finite value, which
will be different for different drugs:
 For a partial agonist, / is small, so that only a small proportion of the
occupied receptors will be activated (even when the receptor occupancy (PA)
approaches 100%). - Compared to a full agonist, whose / is large and most
of the occupied receptors will be activated.
 Thus, the constant / is a measure of efficacy.

The “two-state hypothesis”: (See Rang, Dale and Ritter and Miller)

This is an alternative explanation of drug – receptor interaction.

Receptors may show constitutive activation. This means the R* state can exist without
any ligand bound. There thus exists an equilibrium between R and R* states prior to any
drug added. The shift of this equilibrium is far to the left at this stage (see next page).
The added drug thus encounters an equilibrium mixture of R and R*:

 If it has higher preference for R*, the drug will cause a shift of the equilibrium
towards R*. It will thus promote activation and is thus classed as an agonist. If its
preference for R* is very large, nearly all of the occupied receptors will adopt the R*
state, and the drug will be a full agonist (positive efficacy). Partial agonists will have a
lower preference for R* c/f full agonists.

 If it has a higher preference for R, it will shift the equilibrium towards R, and it is
called an inverse agonist (negative efficacy). Eg = some drugs at GABAA (cause
anxiety, convulsions etc. Even flumazenil is thought to have some inverse agonist
effects). Other examples are drugs acting at canniboid and dopamine receptors
(Rang+Dale).

 If it shows no preference, the prevailing R:R* equilibrium will not be disturbed, and
the drug will be a competitive antagonist (zero efficacy).

So, we can therefore think of efficacy as a property determined by the relative affinity of
a ligand for R and R*. This is known as the “two-state hypothesis” and is another way to
explain drug-receptor interaction as well as the concept of inverse agonists.

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To summarize:

 Full agonists, that can produce maximum effects, have high efficacy.
 Partial agonists have intermediate efficacy.
 Antagonists have zero efficacy.
 According to the “two-state model”, efficacy reflects the relative selectivity of the
ligand for the resting and the activated states of the receptor. Agonists show
selectivity for the activated state and neutral antagonists show no selectivity, but
compete with agonists.
 Inverse agonists show selectivity for the resting state of the receptor. This is only
of significance in unusual situations where the receptors show constitutive
activity (and where this baseline activity has significant physiological effect).
 In general though: Receptor affinity relates to potency and intrinsic activity
(ability to activate receptor once bound), relates to efficacy.

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 The log Dose – response curve: (see later for detail under quantitative aspects)

Efficacy is reflected on the y-axis.

Potency of drug is reflected by its position along the x-axis (i.e. left shift = more potent).

Factors that influence Potency are:

 Affinity for R ( affinity moves curve parallel to the Left and vice versa).

 Pharmacokinetic factors: Absorption, Distribution, Metabolism + Elimination.

For clinical purposes, potency is not that NB, as long as the effective dose can be given
conveniently. Doses needed to produce a specified effect = termed effective dose or ED.
It is usually given as the effective dose needed to produce that effect in a given
percentage of patients and is thus a median dose. Eg ED50 or ED90, MAC, etc. (note the
“50” and “90” are not the degree of response! ). - See addendum re EC50 vs ED50

Slope of the curve and Therapeutic Index:

 In above dose-response curve, the slope of the curve is influenced by the number
of R’s that must be occupied before an effect occurs (threshold of occupancy).
Eg: if a drug must occupy a majority of R’s before response occurs, slope will be
steep ( NMB’s + volatiles).

 Drugs with steep dose-response curves, imply that small increases in dose
intense increases in response. Additionally it also means that the difference b/w
therapeutic dose and toxic dose may be small (low therapeutic index).
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Therapeutic index (TI) = margin of safety, and is the difference b/w dose of drug that
produces desired effect and dose that produces undesired effects. In laboratory,
TI = defined as ratio b/w median lethal dose and median effective dose ( LD50/ED50 ).

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 Drug Antagonism

Above discussion on competitive antagonism does not cover all the mechanisms involved
in drug antagonism.

Mechanisms of drug antagonism: (NB for viva’s + SAQ’s) See Rang, Dale and Ritter

 Competitive antagonism: Reversible or irreversible competitive antagonism.

 Non-competitive antagonism: i.e. block in the receptor-effector linkage / or
binding to non-overlapping (allosteric) site on same receptor.
 Chemical antagonism:
 Pharmacokinetic antagonism:
 Physiological antagonism:

Competitive antagonism: (Receptor blockade)

There is competition for the same primary receptor binding site:

 Reversible competitive antagonism
 Irreversible competitive antagonism (or non-equilibrium competitive antagonism)

Reversible competitive antagonism: Key features = parallel right shift of the log [ ] – effect
curve of the agonist, without any reduction in the maximal response (ie block can be overcome
with increasing dose of agonist). Another feature is a linear Schild plot (see below under
quantitative aspects). In effect the agonist is able to displace the antagonist from the receptors,
although it cannot evict a bound antagonist. Displacement occurs because, by occupying a
proportion of the vacant receptors, the agonist reduces the rate of association of the antagonist
with the R. Consequently the rate of dissociation temporarily exceeds that of association 
overall antagonist occupancy falls.

Irreversible competitive antagonism: Occurs when the antagonist dissociates very slowly, or
not at all, from the R’s. The result is that no change in the antagonist occupancy takes place when
agonist added (Non-competitive antagonism should be reserved for antagonism that does not
involve occupation of the primary binding site). If the antagonist occupies a fraction (P B) of R’s,
then no matter how high the agonist [ ], the agonist occupancy cannot exceed (1- P B), so the
antagonism is non-surmountable. Irreversible competitive antagonism occurs with drugs that
possess reactive groups which form covalent bonds with the R. eg = phenoxibenzamine* at
alpha adrenoreceptors, omeprazole at proton pumps.
Irreversible enzyme inhibitors are clinically used, eg aspirin, MAOI’s.

On a log dose-response curve, the slope and maximum achievable response of the
agonist will decrease in the presence of an irreversible competitive antagonist.

*Phenoxibenzamine has also been shown to have non-competitive irreversible antagonistic properties via
allosteric interaction with alpha receptors (ie binding to the non-primary binding site)

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Non-competitive antagonism: (ie not competing for same primary binding site on receptor)

Possible mechanisms may be:

- Modulation of signal transduction. I.e. Can be the situation where the
antagonist blocks at some point the chain of events that leads to response by
the agonist (but not competing directly with the receptor binding site) eg CCB
like verapamil prevent influx of calcium thru cell membrane and thus blocks
non-specifically the contraction of smooth muscle produced by other drugs (eg
adrenaline).
- Or may be that the antagonist causes a change in affinity of the receptor for the
agonist. Eg Gallamine (NMB) causes tachycardia by decreasing the affinity of
muscarinic Ach-receptors for acetylcholine (agonist).
- Or antagonist binding to a distinct non-overlapping site on the receptor
macromolecule (a.k.a. allosteric interaction). e.g. Flumazenil vs Benzo's

As is the case with irreversible competitive antagonists, the effect will be to reduce the
slope and maximum height of the agonist log [ ] – effect curve when a non-competitive
antagonist is added (some degree of Right-shift might also occur though – Rang + Dale).

Chemical antagonism:

Two substances combine in solution, which result in the loss of the drug-effect. This is
uncommon and examples are: Chelating agents that bind heavy metals ( eg dimercaprol,
desferrioxamine) and neutralizing antibodies against protein mediators such as cytokines
+ growth factors, digitalis antibodies. Sugamadex to reverse NDNMB’s, PraxabindR to
reverse dabigatran.

Pharmacokinetic antagonism:

Here the antagonist effectively reduces the [ ] of the agonist at its site of action (by affecting
A.D.M.E of the agonist). For example, the rate of metabolism can be increased as what happens
with liver microsomal enzyme induction. Eg Phenytoin, steroids etc which increases the
metabolism of rocuronium. Alternatively the rate of absorption of the active drug from
the GIT may be reduced, or the rate of renal excretion increased (see Pharmacokinetics
for detail).

Physiological antagonism:

This describes the interaction of two drugs whose opposing effects result from actions at
their respective (distinct) receptors, which tend to cancel each other. Eg histamine (H2)
and omeprazole on gastric acid secretion, histamine (H1) and adrenaline (alpha and beta)
on the CVS and respiratory systems (eg anaphylaxis), glucagon and beta blockers,
calcium and potassium etc…

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 Desensitization to drugs

When drugs are given repeatedly or continuously, the response to the drug might
gradually diminish.

Terminology:
 Tachyphylaxis refers to when this diminishing effect in response occurs rapidly,
eg over a course of minutes.
 Tolerance refers to the same process, but over a more gradual time course, eg
days or weeks.
 Refractoriness is sometimes used in relation to loss in therapeutic efficacy.
 Drug resistance is sometimes used to describe loss of effectiveness of
antimicrobal or anti-tumour drugs.

Mechanisms involved:

Usually, pharmacodynamic or pharmacokinetic mechanisms involved:

 Change in receptors (PD)

 Loss of receptors (PD)
 Physiological adaptation (PD)
 Exhaustion of mediators (PD)
 Increased metabolic degradation (PK)
 Active extrusion of drug from cells (eg in chemotherapy)

 Change in receptors:

With R’s coupled to ion channels, desensitization can be rapid and pronounced.
At the NMJ, the desensitized state is caused by a slow conformational change in the R,
resulting in tight binding of the agonist molecule without the opening of the ionic ch.

Another, slower mechanism by which ion channels become desensitized, is the

phosphorylation of intracellular regions of the receptor protein.

Receptors linked to 2nd messengers ( eg G-linked) also show desensitization. Eg Beta

Adrenoreceptors, where phosphorylation of the receptor interferes with the ability to
activate the 2nd messenger cascade. Opioid tolerance is another such example.

 Loss of receptors:

Aka as down regulation. Prolonged exposure to a drug often leads to a gradual decrease in the number of
receptors expressed on the cell surface, eg beta receptors. This is a slower process than the “uncoupling”
from 2nd messengers as described above (no of B-receptors can fall by 10% after only 8hrs of isoprenaline
infusion in studies, and take several days to recover). Mechanism involved = endocytosis by patches of the
membrane.
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 Exhaustion of mediators:

Desensitisation may be associated with depletion of an essential intermediate substance

in the signal conduction pathway. Eg amphetamine, which acts via releasing amines (eg
NA) from nerve terminals, can show marked tachyphylaxis secondary to the amine stores
becoming depleted.

 Increased metabolic degradation:

Eg tolerance to alcohol and barbiturates occurs partly due to repeated administration

causing enzyme induction  lower plasma [ ]’s. The contribution to tolerance due to this
mechanism is modest c/f to other mechanisms involved in the substantial tolerance that
can occur to these drugs.

 Physiological adaptation:

Decrease in the response to a drug can occur because it is offset by a homeostatic

response of the body.
EG the BP-lowering effect of thiazide diuretics is limited because of a gradual activation
of the renin-angiotensin-aldosterone system. Homeostatic mechanisms are very
common, and if occur slowly, the result will be a gradual development of tolerance.
Eg , many s/e’s of drugs such as drowsiness or nausea may subside with continuous use
of the drug. Some of the mechanisms involved in physiological adaptation are not well
understood.

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 Graded vs Quantal drug responses

Responses to drugs can also be classified as being either graded or quantal in nature:

 Graded: There is an increasing magnitude in response with increasing drug dosage.

Most drugs display this type of action.

Quantal: In some cases, there is an all-or-nothing response where, once a certain level
of receptor occupancy is reached, the response is triggered. Below this
threshold, there is no response. Quantal responses are subject to inter-
individual variability, whereby different [ ]’s of a drug will be required to
trigger the response in different individuals. The frequency of the response in
the population now becomes the important variable in describing quantal
effects. If number of pts who responds is plotted @ the [ ] of drug to trigger
that response, a Gaussian distribution curve may or may not result. These
curves are hard to interpret, however, if the relationship is re-plotted in the
form of cumulative % response @ dose, a sigmoid curve results, which
resembles the log-dose – response curves as with graded responses. These are
much easier to manipulate and is linear b/w the points of 20% and 80%,
allowing ED50, ED95 etc to be calculated. Eg of a quantal response might be
dose of iv induction agent to produce loss of consciousness, nerve blockade...`

The ultimate quantal response is perhaps mortality…

Graded Dose-response relationship: A majority of drugs produce graded response i.e. the intensity of effect increases
with the dose or concentration of drug. The response can be measured on a continual basis in such cases and it is easy
to establish a linear relationship between drug concentration and intensity. E.g. Increased HR with adrenaline.

Quantal Dose-response relationship: For certain other drugs, the responses are not observed on a continuous basis.
Such drugs may either show their effect or not at all – for example, prevention of seizures by phenytoin. Such responses
are called quantal or all-or-none.

Establishing a concentration-response relationship in such circumstances is difficult but can be developed in terms of the
frequency with which a particular event occurs at a given drug concentration.
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 Mechanisms of action of General Anaesthetics

To a large extent this is still uncharted waters even though we’ve been using the stuff for
around 150 yrs!
There are a few theories and postulations, this makes good bedtime reading and I will just
gloss over some of it.

During the 80’s and 90’s, ion channels became popular as potential molecular targets to
mediate the CNS effects of general anaesthetics.
Especially for the intravenous agents, GABAA and NMDA receptors seems to be the
most likely targets, but possibly also for the volatiles.
This is because of their ubiquitous distribution and important physiological roles in the
CNS.
Recent evidence suggests a variety of other ion channels, especially with regards to the
volatiles. Eg = “leak K-channels”, HCN family of channels which are responsible for
“pacemaker currents”, + voltage gated Na-ch’s, especially at critical presynaptic sites.

Pharmacological criteria that a target molecule (receptor or other) must meet to qualify as
a candidate for mediating actions of the general anaesthetics:
 The general anaesthetic must alter the fx of the R at behaviorally relevant [ ]’s
 The R must be expressed at the appropriate anatomical locations.
 NB: If the drug shows stereoselective effects in vivo, these should be mirrored by
anaesthetic actions at the R in vitro. This represents one of the most powerful
tests for the relevance of a putative anaesthetic target. General anaesthetic
stereoselectivity demolished the old traditional “ lipid theories” of anaesthetic
action. Stereoselectivity has been used to support evidence for GABAA as a target
R in mediating the actions of etomidate, pentobarbitone and the steroid
anaesthetics (alphaxalone, = veterinary drug), as in vivo potency and activity at
the GABAA R display identical trends. The inhibitory stereoselectivity of
ketamine isomers is paralleled by the inhibitory action of the stereoisomers at the
NMDA R.

It is also accepted that general anaesthetics have effects at both pre-and postsynaptic sites. At
inhibitory synapses mediated by GABAA, the predominant effect seems to be an increase in the
postsynaptic effect of the neurotransmitter at lower, clinically relevant anaesthetic [ ]’s, at which
there may also be an increase in the frequency of spontaneous release of GABA. At higher [ ]’s,
both pre- and postsynaptic fx may be depressed.
At excitatory synapses mediated by glutamate, the main effect seems to be a decrease in the
postsynaptic effect of the neurotransmitter that is observed at higher anaesthetic [ ]’s.
In most cases, = likely due to a combination of either direct hyperpolarization of the postsynaptic
neurons and/or a decrease in the spontaneous + evoked release of glutamate.

 Other theories/historical: - Membrane lipids as targets: (Meyer-Overton rule for gases)

- Membrane expansion theory.

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 Quantitative aspects of drug-receptor interaction
“The kinetics of pharmacodynamics” 

Governed by Law of Mass action: Rate of chemical reaction = proportional to the

product of the concentrations of reactants.

 For the Binding reaction:

k-1
A + R  AR
Drug free receptor k+1 complex
(xA) (Ntot- NA) (NA)

Thus, rate of forward reaction is proportional to xA(Ntot – NA)

Thus, rate of fw reaction is equal to k+1xA(Ntot – NA)

And backward is: k-1NA

At equilibrium, the two rates are equal:

K+1xA(Ntot – NA) = k-1NA

Now, the proportion of R’s occupied, or occupancy (pA) = NA/Ntot

xA____
Substituting from above: pA = xA + k-1/k+1

The equilibrium constant for binding reaction, KA = k-1/k+1 ,

Substituting again, gives the important Hill–Langmuir equation:

xA/KA___
pA = xA/KA + 1 ( graph on next page = drawn according to this equation )

KA is a characteristic of both the drug and the receptor. It has the dimensions of
concentration and is numerically equal to the concentration of drug needed to occupy
50% R sites at equilibrium.

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 A) = Rectangular hyperbole
B) = Symmetrical sigmoid curve if concentration is logarithmically charted.

The higher the affinity of the drug for the R, the lower the value for KA.

Binding when more than one drug (ligand) is present:

Suppose 2 drugs, A + B that bind to same R with equilibrium constants KA and KB

respectively, are present at concentrations xA and xB. Now if the 2 drugs compete for the
same R, then by the same reasoning as above’s one-drug binding kinetics, the occupancy
for drug A is given as:

xA/KA_______
PA = xA/KA + xB/KB + 1

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 xA/KA_______
Comparing PA = xA/KA + xB/KB + 1 with the Hill equation, shows that binding
drug B, decreases the occupancy of drug A, as expected. The diagrams below shows
binding curves for A in presence of a reversible and irreversible competing antagonist.

Note the parallel R-shift without any change of slope or maximum. This is comparable to
dose-response curves where a reversible competitive antagonist is added to an agonist.

The extent of the R-shift on a logarithmic scale, represents the ratio (rA ), by which [A]
must be increased to overcome the competition by B.
rA = xA/xA , where xA is the increased concentration of A.

xA/KA_______
Rearranging, PA = xA/KA + xB/KB + 1 , shows that :

rA = xB/KB + 1 = known as the Schild equation.

Thus, rA depends only on the [ ] and equilibrium constant of the competing drug.

Schild equation can be logarithmically expressed as :

log(r-1) = logxB – logKB

( ie in form of y =mx + b, the equation for a straight line….)

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A plot of log(r-1) vs logxB should thus give a straight line with unit slope and an
abscissal intercept equal to logKB. This plot is known as a Schild plot.

To summarize the characteristics of rA :

 Dependant on the concentration and equilibrium constant of the competitive

antagonist and not on the size of the response that is chosen as a reference point
for the measurements.

 It increases linearly with xB, and the slope of a plot of (r-1) against xB is equal to
1/KB. This relationship, being independent of the characteristics of the agonist,
should be the same for all agonists that act on the same population of receptors.

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 More examples of drug-response curves

A + B are both agonists, A more potent.

C is a partial agonist (less efficacious) and has lower potency than A and B. Addition of
reversible competitive antagonist, D, to A shifts A’s curve to right ( eg reduces potency),
but without altering its height ( eg same efficacy).
A non-competitive antagonist, E, shifts curve to right, reduces its height and alters its
slope.

(From: Foundations of Anesthesia)

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 Addendum:

Re: EC50, ED50 and ED95:

Def: EC50: Half maximum effective concentration:

The concentration of a drug at which 50% of its maximum response is observed and
applies to graded drug responses.

Thus, the term half maximal effective concentration (EC50) refers to the concentration
of a drug, which induces a response halfway between the baseline and maximum after a
specified exposure time. It is commonly used as a measure of drug's potency.

The EC50 of a graded dose response curve therefore represents the concentration of a
compound where 50% of its maximal effect is observed. The EC50 of a quantal dose
response curve represents the concentration of a compound where 50% of the population
exhibits a response, after specified exposure duration.

Def: ED50: Median effective dose:

The ED50 is the "median effective dose" that produces a quantal effect (all or nothing) or
desired effect in 50% of the population that receives it (median referring to the 50%
population base). It is also sometimes abbreviated as the ED50, meaning "effective dose,
for 50% of people receiving the drug". Note: ED50 can thus be used in both quantal as
well as graded responses, as long as the desired effect as a percentage of the population
is expressed against the log-dose.

Def: The ED95 is the dose required for desired effect in 95% of the population exposed
to it.

However, with respect to non-depolarising neuromuscular blocking agents: ED95 is the

median dose required to achieve a 95% reduction in maximal twitch response from
baseline, in 50% of the population. The single twitch response occurs when applying a
square wave "supra-maximal" current, using a nerve stimulator, to the ulnar nerve and
measuring twitch of the adductor pollicus.
Thus, the more accurate use of the term in this regard would be "ED5095 (ie the ED50 for
95% twitch height reduction). Notwithstanding, usage of the term "ED95" has stuck in
this context.

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More sample curves:
23
 Old Questions:

Draw and explain the characteristics of a log dose-response curve that describes
the major clinical effect of rocuronium. Describe how factors encountered in
clinical practice may alter this curve. (2014a)